The generation of memory T cells is the end result of a productive immune response. We propose that the survival of just a few effector cells is instructed during the initial activation process. Characterization of this instructional process has been significantly hampered by the inability to identify precisely which primary responder cells will differentiate into memory T cells. Recently we have shown that CD8alpha/alpha expression on a selected subset of CD8aa+ primary effectors uniquely marks the precursors of memory CD8 T cells. This new insight provides for the first time a powerful tool to evaluate the instructional process of CD8 T cell memory formation. In the first Aim of this grant we will define the role of subsets and maturation stages of Dendritic Cells (DC) in generating the CD8alpha/alpha+ memory precursor population. In a second Aim, we will address the role of T cell help in the generation of CTL memory. The contributions of conventional CD4 Th help and help provided by NKT cells will be investigated. In a third Aim we will focus on the CD8 effector T cells themselves, and evaluate the extent to which the quality of the TCR activation signals contributes to the initial selection of CD8alpha/alpha+ memory precursor cells and to the further selection and interclonal competition during repeated antigenic stimulations. Elucidating the initial events that lead to effective memory are extremely important for the design of vaccines and drugs that stimulate optimal immunity against infections and cancers, or treatments that dampen the response in autoimmunity or transplantation. The experiments in this proposal use lymphocytic choriomeningitis virus (LCMV), an arena virus. Understanding the basic mechanism of CDS memory formation to viruses and other pathogenic agents is highly relevant to the biodefense needs facing the United States today.